2-(N-methyl-propanamine)-3-(2-naphthol)thiophene, an impurity of duloxetine hydrochloride
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsSantiago Ini, Alexei Ploutno, Anita Liberman, Mili Abramov, Osnat Porter-Kleks, Dina Berezovsky
Life of this patent
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Abstract
The invention encompasses 2-N-methyl-propanamine)-3-(2-naphthol) thiophene, a duloxetine hydrochloride impurity, as well as its use as a reference marker and reference standard.
Claims25
Isolated 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene.
A process for preparing 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene comprising:
- a) heating a mixture of duloxetine and at least one solvent, wherein the solvent is a C2-C8 ether, a C5-C8 aliphatic or C6-C12 aromatic hydrocarbon, a C1-C8 alcohol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, 1-methyl-2-pyrrolidinone, acetonitrile or propylene glycol methyl ether;
- and
- b) maintaining the mixture for a period of time sufficient to obtain 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene.
A process for preparing duloxetine hydrochloride having less than about 0.08% area by HPLC of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene comprising:
- a) providing a mixture of duloxetine hydrochloride having more than about 0.08% area by HPLC of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene in at least one polar solvent, wherein the polar solvent is a C2-5 ketone, C2-5 alkyl ester, C2-8 alkyl ether or C2-8 alkanol;
- and
- b) maintaining the mixture for a period of time sufficient to obtain duloxetine hydrochloride having less than about 0.08% area by HPLC of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene.
A method of using 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene as a reference marker to analyze the purity of duloxetine hydrochloride comprising:
- a) providing a reference sample comprising duloxetine hydrochloride and 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene;
- b) analyzing the reference sample by HPLC and determining the relative retention time of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene compared to duloxetine hydrochloride;
- c) analyzing a sample of duloxetine hydrochloride by HPLC and determining the relative retention times of the contents of the sample as compared to duloxetine hydrochloride;
- and
- d) comparing the relative retention times calculated in step c) to the relative retention time calculated in step b) for 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene, wherein if any of the relative retention times calculated in step c) are substantially the same as the relative retention time of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene, 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene is present in the sample of duloxetine hydrochloride.
A method of using 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene as a reference standard for determining the amount of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene in a duloxetine hydrochloride sample comprising:
- a) measuring by HPLC the area under the peak corresponding to 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene in a sample of duloxetine hydrochloride having an unknown amount of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene;
- b) measuring by HPLC the area under a peak corresponding to 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene in a reference standard comprising a known amount of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene;
- and
- c) determining the amount of 2-(N-methyl-propanamine)-3-(2-naphthol) thiophene in the duloxetine hydrochloride sample by comparing the area calculated in step a) to the area calculated in step b).
A quantification method for determining the amount of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene in a duloxetine hydrochloride sample comprising:
- a) measuring by HPLC the area under the peak corresponding to 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene in a sample of duloxetine hydrochloride having an unknown amount of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene;
- b) measuring by HPLC the area under a peak corresponding to duloxetine hydrochloride in a reference standard having a known amount of duloxetine hydrochloride;
- and
- c) determining the amount of 2-(N-methyl-propanamine)-3-(2-naphthol) thiophene in the duloxetine hydrochloride sample by comparing the area calculated in step a) to the area calculated in step b).
An HPLC method for determining the amount of 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene in a sample of duloxetine hydrochloride comprising:
- a) combining a sample of duloxetine hydrochloride having 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene with a 1:1 (volume:
- volume) mixture of water and acetonitrile to form a solution, wherein the duloxetine hydrochloride is present in an amount of about 0.2 mg per milliliter of the solution;
- b) injecting the solution of step a) into a Hypersil Gold 150×4.6, 5μ column;
- c) eluting the sample from the column for about 60 min with a 63:28.8:8.2 mixture of 0.02 M KH2PO4:
- methanol:
- tetrahydrofuran and a 20:80 mixture of 0.02M K2HPO4:
- acetonitrile as an eluent;
- and
- d) measuring the 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene content of the sample with a UV detector at 230 nm wavelength.
Dependencies are inferred from the claim text.